The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions

Christopher C. Dvorak, Elie Haddad, Jennifer Heimall, Elizabeth Dunn, Morton J. Cowan, Sung Yun Pai, Neena Kapoor, Lisa Forbes Satter, Rebecca H. Buckley, Richard J. O'Reilly, Sharat Chandra, Jeffrey J. Bednarski, Olatundun Williams, Ahmad Rayes, Theodore B. Moore, Christen L. Ebens, Blachy J. Davila Saldana, Aleksandra Petrovic, Deepak Chellapandian, Geoffrey D.E. CuvelierMark T. Vander Lugt, Emi H. Caywood, Shanmuganathan Chandrakasan, Hesham Eissa, Frederick D. Goldman, Evan Shereck, Victor M. Aquino, Kenneth B. Desantes, Lisa M. Madden, Holly K. Miller, Lolie Yu, Larisa Broglie, Alfred Gillio, Ami J. Shah, Alan P. Knutsen, Jeffrey P. Andolina, Avni Y. Joshi, Paul Szabolcs, Malika Kapadia, Caridad A. Martinez, Roberta E. Parrot, Kathleen E. Sullivan, Susan E. Prockop, Roshini S. Abraham, Monica S. Thakar, Jennifer W. Leiding, Donald B. Kohn, Michael A. Pulsipher, Linda M. Griffith, Luigi D. Notarangelo, Jennifer M. Puck

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. Results: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). Conclusions: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

Original languageEnglish (US)
Pages (from-to)547-555.e5
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Feb 2023


  • Omenn syndrome
  • SCID
  • Severe combined immunodeficiency
  • leaky/atypical SCID
  • newborn screening
  • typical SCID

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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